Approaches to the synthesis of 2′-thio analogues of pyrimidine ribosides

Abstract

2′-Deoxy-2′-mercaptouridine (1) was obtained in 75% isolated yield by heating 2′-deoxy-2′-(4-methoxybenzylthio)uridine (4a) with phenol in trifluoroacetic acid solution. When triphenylmethanol or 9-phenylxanthen-9-ol (5) was added to the products before work-up, compound (4c) or (4d) was obtained. Compound (4d) was also obtained in satisfactory overall yield from crude (1), prepared in two steps from 2′-deoxy-2′-(t-butylthio)uridine (4b). Treatment of compound (4d) first with acetic anhydride in pyridine and then with phosphoryl trichloride, triethylamine, and 1,2,4-triazole in acetonitrile gave the triazolo compound (10) in 73% overall yield. Reaction between compound (10) and ammonia in dichloromethane [or dimethylamine in dioxane] followed by methanolic ammonia gave the cytidine derivative (11a)[or (11b)] in good yield. When compounds (11a) and (11b) were allowed to react with hydrochloric acid in 2-mercaptoethanol solution at room temperature, the hydrochloride salts of 2′-deoxy-2′-mercaptocytidine (2a) and its 4,4-di-N-methyl derivative (2b) were obtained in high isolated yields. The latter compounds readily underwent aerial oxidation in the presence of triethylamine in methanol solution to give the corresponding dimeric disulphides (12a) and (12b). The NMR spectra of the synthetic products are discussed.